Naturally acquired immunity is critical in modulating morbidity and mortality from falciparum malaria in endemic areas, where some individuals are infected hundreds of times per year. Humoral responses to Plasmodium falciparum (Pf) are a critical component of this immunity, and Pf-specific memory B cells (MBCs) are likely important in the development and maintenance of an effective response. Unfortunately, protection from clinical disease takes many years to develop, during which time children living in endemic areas experience multiple episodes of symptomatic malaria, resulting in over 1 million deaths annually. Why does antimalarial immunity develop so slowly? One potential explanation is that Pf infection interferes with the development of effective B cell memory. An atypical phenotype of MBC, exhibiting evidence for lower affinity maturation and less capacity for differentiation into antibody secreting cells, has recently been described in the blood of HIV infected subjects. Recent studies have demonstrated that people living in malaria endemic areas have elevated frequencies of similar atypical MBCs, but the relationship between Pf exposure and frequencies of atypical MBCs has not been investigated in detail. Moreover, it is unclear what the consequences of these cells are in malaria infected individuals. We hypothesize that frequent exposure to Pf results in the selective diversion of Pf-specific B cells into an atypical MBC phenotype, delaying the acquisition of protective immunity to Pf. We are in a unique position to test this hypothesis, with access to a well characterized cohort of subjects living in an area of high but heterogeneous malaria transmission intensity and established laboratory infrastructure. Pf transmission intensity at our site in Tororo, Uganda ranks among the highest in the world, and preliminary data from this site suggest that affinity of Pf-specific antibody responses may be compromised in this setting. We will test our hypothesis with the following Specific Aims: 1) To measure the association between Pf exposure and enrichment of atypical memory B cells in children living in a high transmission region of Uganda.; and 2) To measure the association between enrichment of atypical memory B cells and serological and parasitological evidence of protective humoral immunity to malaria. We anticipate this study will show that increased exposure to Pf is associated with increased defects in B cell memory, characterized by higher proportions of Pf-specific MBCs showing an atypical phenotype and evidence of reduced Pf-specific antibody affinity and ability to control blood stage parasites. If so, counter to prevailig notions that malaria control efforts will delay the acquisition of immunity, strategies designed to reduce exposure may have a positive impact on immunity. In addition, methods to characterize Pf-specific B cells developed in this study will have broad application for investigating humoral immunity to Pf.